P1526: AUTOIMMUNE HEMOLYTIC ANEMIAS: RELATIONSHIP BETWEEN SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOKINE GENES AND CLINICAL/HEMATOLOGICAL PARAMETERS
Authors: A. Zaninoni, B. Fattizzo, J. Giannotta, E. Fermo, P. Bianchi, N. Cecchi, W. Barcellini
Journal: HemaSphere (2022)

Background: Autoimmune hemolytic anemia (AIHA) is highly heterogeneous and involves several pathogenic mechanisms including autoantibody production, complement activation, and cytokine dysregulation. Hb levels at baseline and the degree of bone marrow compensation are the main predictors of outcome. The contribution of high, intermediate, and low producer genetic profile cytokine genes may give further insights into the pathogenesis of the disease. Aims: To evaluate the frequency of cytokine single nucleotide polymorphisms (SNPs) in warm (wAIHA) and cold agglutinin disease (CAD) and their relationship with clinical and hematological parameters, including the degree of anemia, treatment refractoriness and number of therapies lines. Methods: We investigated SNPs of five cytokine genes [tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, transforming growth factor (TGF)-beta, interleukin (IL)-6 and IL-10] in 72 Italian warm AIHA patients, using the Cytokine Tray (One Lambda, Canoga Park, CA) according to the manufacturer’s recommendations. Allele and genotype frequency results were compared to those described in the Italian population by Uboldi de Capei et al. (2003) and Poli et al. (2002). Results: One hundred and twenty AIHA patients have been evaluated: median age 63 years (range 17-90), classified as wAIHA (n=75) and CAD (n=45). Demographic and hematological characteristics of patients are described in Figure 1A. Regarding cytokine SNP frequencies (Figure 1B), we observed that the TNF-alpha-308 high producers genotypes (G/G and G/A) were significantly more frequent in AIHA patients (37% vs 16%, p=0.0003 or 37% vs 23%, p=0.01) and in wAIHA (43% vs 16%, p<0.0001 or 43% vs 23%, p=0.0014) compared to controls. No differences were observed in CAD patients versus controls. Likewise, no significant differences between AIHA (including wAIHA and CAD subtypes) and controls were noted regarding other cytokine SNPs. Concerning the clinical severity at presentation, the frequency of TGF-beta (82% vs 58%, p=0.01) and IL-10 (17% vs 5%, p=0.03) high producers was higher in patients with Hb ≤7.5 g/dL (median of all AIHA) versus those with less severe presentation. Similarly, the frequency of high/intermediate IFN-gamma producers was higher within the group with Hb levels ≤7.5 g/dL at onset (75% vs 58%, p=0.03). No characteristic patterns were observed regarding IL-6 and TNF-alpha. Finally, the patterns of TNF-alpha and TGF-beta production were differently distributed considering the number of therapy lines: the first both in all AIHA and in CAD patients (p=0.004 and p=0.01, respectively), the second only in CAD patients (p=0.03). No differences in genotype frequencies of cytokine SNPs were observed regarding the number of relapses. Image:Summary/Conclusion: These preliminary data show that AIHA patients display a more pro-inflammatory cytokine signature at molecular level (TNF-alpha high producer genotype) as compared to the Italian control population. Moreover, cytokine SNPs were also associated with clinical severity at onset, and requirement of multiple treatments.